A basic understanding of the cell, in health and disease, is essential if we are to understand more complex tissue and organ function. As a result of ion flux and electrical studies of osmotically perturbed Amphiuma erythrocytes, obligatorily coupled, electroneutral alkali metal/H exchange pathways have been identified as being responsible for volume regulation by that cell. Functionally similar pathways have been reported to participate in cell growth, intracellular pH regulation and epithelial fluid and electrolyte transport. By virtue of the central role played by alkali metal/H (particularly Na/H) exchange in a variety of physiologically important processes an increased understanding of the kinetics and control of the pathway is of interest to both clinical and basic scientists. The proposed studies of the activation, control and pharmacological sensitivity of alkali metal/H exchange using the Amphiuma red blood cells as a model system are therefore of general interest and biological importance. In addition to the above, studies intended to evaluate the contribution of electroneutral alkali metal transport to cell volume disturbances associated with ischemia and anoxia are proposed. These studies will be performed upon perfused rabbit heart and will employ pressure/volume measurements to evaluate volume distributions and NMR to evaluate changes in intracellular alkali metal ion content. The information gained in the red blood cell studies regarding the kinetics, control and pharmacology of Na/H exchange will be used on a predictive and interpretive basis in assessing the participation of that pathway in cardiac cell volume disturbances. To the extent that Na/H exchange contributes to volume disturbances associated with pathological conditions the information obtained in the red blood cell studies is clinically significant.